Obesity is an increasingly important risk factor for cardiovascular disease in men and womenand is[unreadable] associated with the premature development of atherosclerosis, and increased risk of stroke. A classical[unreadable] perspective of cardiovascular risk does not adequately explain all of the cardiovascular events associated with[unreadable] obesity. Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are one of the biochemical[unreadable] hallmarks of obesity and likely contribute to the increased risk of atherothrombotic events in patients with[unreadable] obesity. For the last several years, this laboratory has been involved in a series of basic and clinical[unreadable] investigations that have helped to define the molecular physiology of PAI-1 and its role in the arterial[unreadable] thrombosis and arteriosclerosis. The central hypothesis of this proposal is that vascular PAI-1 excess[unreadable] promotes the development of intravascular thrombosis. In this proposal, we will test the hypothesis that[unreadable] secreted factors from adipocytes have autocrine, paracrine, and endocrine effects that have a deleterious[unreadable] effect on the fibrinolytic system, either by enhancing PAI-1 production or impairing endothelial t-PA release.[unreadable] This project will utilize genetic, proteomic, cellular, animal and human experimental systems to define the[unreadable] mechanisms of impaired fibrinolysis in obesity. From a public health perspective, there is no greater threat to[unreadable] America's cardiovascular health than the epidemic of obesity. It is anticipated that this study will provide[unreadable] new insights into the molecular mechanisms that contribute to the development of fibrinolytic dysfunction and[unreadable] cardiovascular disease in obesity.